Mitochondrial permeabilization relies on BH3 ligands engaging multiple prosurvival Bcl-2 relatives, not Bak (original) (raw)
Article| April 23 2007
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
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The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Search for other works by this author on:
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Search for other works by this author on:
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Search for other works by this author on:
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Search for other works by this author on:
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Search for other works by this author on:
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
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Rachel T. Uren
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Grant Dewson
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Lin Chen
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Stephanie C. Coyne
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
David C.S. Huang
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Jerry M. Adams
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
Ruth M. Kluck
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia
R.T. Uren and G. Dewson contributed equally to this paper.
R.T. Uren's present address is Genes to Cognition Programme, Wellcome Trust, Sanger Institute, Cambridge CB10 1SA, UK.
Abbreviations used in this paper: BH, Bcl-2 homology; MLM, mouse liver mitochondria; XEM, Xenopus egg mitochondria.
Received: June 13 2006
Accepted: March 20 2007
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2007
J Cell Biol (2007) 177 (2): 277–287.
The Bcl-2 family regulates apoptosis by controlling mitochondrial integrity. To clarify whether its prosurvival members function by sequestering their Bcl-2 homology 3 (BH3)–only ligands or their multidomain relatives Bak and Bax, we analyzed whether four prosurvival proteins differing in their ability to bind specific BH3 peptides or Bak could protect isolated mitochondria. Most BH3 peptides could induce temperature-dependent cytochrome c release, but permeabilization was prevented by Bcl-xl, Bcl-w, Mcl-1, or BHRF1. However, their protection correlated with the ability to bind Bak rather than the added BH3 peptide and could be overcome only by BH3 peptides that bind directly to the appropriate prosurvival member. Mitochondria protected by both Bcl-xl–like and Mcl-1 proteins were disrupted only by BH3 peptides that engage both. BH3-only reagents freed Bak from Bcl-xl and Mcl-1 in mitochondrial and cell lysates. The findings support a model for the control of apoptosis in which certain prosurvival proteins sequester Bak/Bax, and BH3-only proteins must neutralize all protective prosurvival proteins to allow Bak/Bax to induce mitochondrial disruption.
The Rockefeller University Press
2007
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